The present invention relates to novel carbamates, ureas, and pharmaceutically acceptable salts thereof; compositions comprising the carbamate, urea, or a pharmaceutically acceptable salt thereof; and methods for treating or preventing cancer, inflammation, or a viral infection comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of the carbamate, urea, or pharmaceutically acceptable salt thereof.
Protein-nucleic acid interactions are involved in many cellular functions, including transcription, RNA splicing, RNA maturation, telomere synthesis, and mRNA translation. Molecules that can bind with high affinity to specific sequences of single- or double-stranded nucleic acids have the potential to interfere with these interactions in a controllable way, making them attractive tools for molecular biology and medicine. Nucleic acids, and in particular RNA, however, can fold into complex tertiary structures consisting of local motifs such as loops, bulges, pseudoknots and turns (Chastain, M. and Tinoco, I., Jr. (1991) Progress in Nucleic Acid Res. and Mol. Biol. 41:131-177; Chow, C. S. and Bogdan, F. M. (1997) Chemical Reviews 97:1489-1514), which are critical for protein-RNA interactions (Weeks, K. M. and Crothers, D. M. (1993) Science 261:1574-1577). The dependence of these interactions on the native three-dimensional structure of RNA makes it difficult to design synthetic agents with general, simple-to-use recognition rules analogous to those for the formation of double- and triple-helical nucleic acids. Transcription of the HIV genome during virus replication shows distinct kinetic phases (see e.g., Feinberg et al. (1986) Cell 46:807-817; Kim et al. (1989) J. Virol. 63:3708-3713; Knight et al. (1987) Science 236:837-840; Sodrowski et al. (1986) Nature (London) 321:412-417). The initial products of HIV gene expression are short, multiply spliced mRNAs approximately 1.8 to 2.0 kb in length, which encode the trans-acting regulatory proteins TAT, REV, and possibly NEF. As infection by the virus develops, and the levels of the TAT and REV proteins rise in the infected cells, mRNA production shifts progressively towards production of a family of singly-spliced 4.3 kb mRNAs encoding ENV and other HIV gene products such as VIF and VPR. To achieve this control of gene expression, the HIV virus relies on the interaction of cellular and virus-encoded trans-acting factors with cis-acting viral regulatory sequences (Dayton et al. (1986) Cell 44:941-947; Fisher et al. (1986) Nature 320:367-371; Feinberg et al. (1986) Cell 46:807-817). Initiation of transcription relies largely on the presence of binding sites for cellular transcription factors in the viral long terminal repeat (LTR) (Garcia et al. (1989) EMBO J. 8:765-778). The virally encoded regulatory proteins TAT and REV exert their activity via cis-acting sequences encoded within HIV messenger RNAs. The trans activation-responsive region (TAR) is required for TAT activity, and is located in the viral long terminal repeat (LTR)between residues +1 and +79 (Muesing et al. (1987) Cell 48:691-701; Emerman et al. (1987) EMBO J. 6:3755-3760; Roy et al. (1990) J Virol. 64:1402-1406 (1990); Berkhout et al. (1989) J. Virol. 63:5501-5504).
The distinct kinetic phases of HIV transcription are now believed to reflect the intracellular levels of the regulatory proteins TAT and REV. As TAT levels rise, increased transcription from the LTR is stimulated by the trans-activation mechanism. This leads to further increases in TAT levels, and also stimulates production of REV. Production of the viral structural proteins begins once REV levels have risen to sufficiently high levels to promote export of messenger RNAs carrying the rev-responsive element (RRE)sequence. Significant levels of HIV gene expression are only achieved in the presence of TAT protein. Experiments strongly suggest that TAT activity requires RNA target sequences. Deletion analysis of the viral LTR showed that TAT activity requires a regulatory element located downstream of the initiation site for transcription, at the 5-terminus of all the mRNA transcripts between residues +1 and +79, called the trans-activation-response region (TAR) (Muesing et al. (1987) Cell 48:691-701; Emerman et al. (1987) EMBO J. 6:3755-3760; Roy et al. (1990) J Virol. 64:1402-1406 (1990); Berkhout et al. (1989) J. Virol. 63:5501-5504). The placement of TAR in a transcribed region suggested that it could function as an RNA rather than as a DNA element. (Muesing et al. (1987) Cell 48:691-701; Emerman et al. (1987) EMBO J. 6:3755-3760; Selby et al. (1989) Genes Dev. 3:547-558; Hauber et al. (1988) J. Virol. 62:673-679; Jakobovits et al. (1988) J. Mol. Cell Biol. 8:2555-2561; Peterlin et al. (1986) Proc. Natl. Acad. Sci. U.S.A. 83:9734-9738).
Furthermore, the TAR RNA sequence forms a highly stable, nuclease-resistant, stem-loop structure (Selby et al. (1989) Genes and Dev. 3:547-558). It appears that the TAR RNA sequence must be transcribed in the nucleus and correctly folded in order for trans-activation to occur (Berkhout (1989) Cell 59:273-282).
And it has been demonstrated that TAT is able to specifically recognize TAR RNA. Binding shows high affinity (Kd=12 nM) and TAT forms one-to-one complexes with TAR RNA (Dingwall et al. (1990) EMBO J. 9:4145-4153). This provides strong evidence for the ability of TAT to stimulate transcription from promoters that carry the TAR sequence by direct binding to TAR RNA. Compounds that bind TAR RNA inhibit the activity of the regulatory protein TAT in the viral growth cycle of HIV and, accordingly, are useful for treating or preventing HIV infection.
Moreover, compounds that bind to specific sequences and/or structures in nucleic acids and thereby modulate or interfere with protein-nucleic acids, and in particular, protein-RNA interactions, are potentially valuable therapeutic agents useful for the prevention and treatment of cancer, and inflammatory conditions, as well as disease arising from viral infection, including HIV infection and AIDS.
Therefore, there is a clear need in the art for compounds that bind RNA and interfere with protein-RNA interactions, and in particular, there is a clear need in the art for compounds that bind TAR RNA.
Citation or identification of any reference in Section 2 of this application is not an admission that such reference is available as prior art to the present invention.
The present invention provides compounds of formula I:
Hxe2x80x94Yxe2x80x94Yxe2x80x94Yxe2x80x94NH2xe2x80x83xe2x80x83I
and pharmaceutically acceptable salts thereof,
wherein each Y is independently a radical having the structure of II, III, or IV: 
each R1 is independently selected from the group consisting of xe2x80x94NH2, xe2x80x94NHC(xe2x95x90NH)NH2, and xe2x80x94CH2C(xe2x95x90NH)NH2;
each m is independently an integer ranging from 3 to 7;
each * is an (R) or (S) chiral center; and
with the proviso that at least one Y is a radical having the structure of IV.
In one embodiment, the compounds of formula I and pharmaceutically acceptable salts thereof are those wherein at least two Y are independently a radical having the structure of IV.
In another embodiment, the compounds of formula I and pharmaceutically acceptable salts thereof are those wherein each Y is independently a radical having the structure of IV.
The compounds of formula I and pharmaceutically acceptable salts thereof are useful for treating or preventing cancer, inflammation, or a viral infection in a patient.
The present invention further provides compositions comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof can additionally comprise a pharmaceutically acceptable vehicle. These compositions are useful for treating or preventing cancer, inflammation, or a viral infection in a patient.
The present invention still further provides a method for treating or preventing cancer, inflammation, or a viral infection in a patient, comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The present invention still further provides compounds of formula V: 
and pharmaceutically acceptable salts thereof,
wherein each R2 is independently selected from the group consisting of xe2x80x94NH2, xe2x80x94NHC(xe2x95x90NH)NH2, xe2x80x94CH2C(xe2x95x90NH)NH2, and xe2x80x94C(O)NE2;
each n is independently an integer ranging from 3 to 7; and
each * is an (R) or (S) chiral center.
The compounds of formula V and pharmaceutically acceptable salts thereof are useful for treating or preventing cancer, inflammation, or a viral infection in a patient.
The present invention still further provides compositions comprising a therapeutically effective amount of a compound of formula V or a pharmaceutically acceptable salt thereof. The compositions comprising a compound of formula V or a pharmaceutically acceptable salt thereof can additionally comprise a pharmaceutically acceptable vehicle. These compositions are useful for treating or preventing cancer, inflammation, or a viral infection in a patient.
The present invention still further provides a method for treating or preventing cancer, inflammation, or a viral infection in a patient, comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound of formula V or a pharmaceutically acceptable salt thereof.
The present invention may be understood more fully by reference to the figures, detailed description, and examples, which are intended to exemplify non-limiting embodiments of the invention.